Philipp Lachenmann: DELPHI Rationale


Walter Hohlweg Prize 2002

Dr. Oliver Treeck

Department of Obstetrics and Gynecology
Medical University of Lübeck

Therapeutic inhibition of HER2 signaling is counteracted by estradiol-induced activation of extracellular signal-regulated kinase in endometrial adenocarcinoma cell lines

Cellular response to estradiol stimuli is mediated both by estrogen receptor binding to estrogen response elements and by non-nuclear actions like activation of mitogen-activated protein kinase signal transduction. Therefore, estradiol stimuli might be able to interfere with the action of antitumoral substances directed against receptor tyrosine kinase signaling.

We investigated the effect of estradiol on the inhibition of HER2 signaling in two human endometrial adenocarcinoma cell lines. Activation of the extracellular signal-regulated kinase (ERK-1/2), a main mediator of HER2 signaling, was measured by means of western blot experiments and estrogen response element activation was determined in transient reporter-gene assays. In endometrial Ishikawa and HEC-1A adenocarcinoma cells, HER2 signaling was inhibited by a therapeutic humanized HER2 antibody only in the absense of estradiol.

We were able to demonstrate, that estradiol counteracted the HER2 inhibition by rapid phosphorylation of ERK-1/2, a kinase downstream the HER2 receptor. The pure antiestrogen ICI 182,780 was able to restore both the therapeutic inhibition of the ERK-1/2 pathway and the antiproliferative action of the HER2 inhibitor in Ishikawa cells. Our data suggest that combinations of therapeutic HER2 antibodies with antiestrogens may be effective in the treatment of endometrial cancer with positive ER- and HER2-receptor status.



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